Drug Delivery and Disposition
The research objectives of Drug Delivery and Disposition are focused on enhancing drug bioavailability of dosage forms for extravascular administration using pharmaceutical-technological approaches (new drug formulations and process technology) as well as biopharmaceutical strategies (based on knowledge of mechanisms underlying drug absorption and hepatobiliary disposition). Significant contributions have been made in the understanding of the physicochemical principles behind formulation strategies for poorly soluble drugs like amorphous solid dispersions, nanoparticles, and mesoporous drug loaded silica. The Laboratory innovates in the development of preclinical models for ADMETox profiling; these model systems include in situ intestinal perfusion in mice (enabling the use of KO and humanized mice in intestinal absorption studies) and hepatocyte-based prediction of drug-induced cholestasis.
|Prof. Patrick Augustijns||Prof. Pieter Annaert||Prof. Guy Van den Mooter|
Drug Delivery and Disposition has a strong track record in the biorelevant profiling of intestinal drug absorption, covering all underlying processes including dissolution, precipitation, degradation and permeation. For this purpose, a wide range of simulation models is available, including the in vitro Caco-2 cell culture system, the Ussing chamber system and the in situ intestinal perfusion system. In addition, Drug Delivery and Disposition is able and licensed to perform whole animal absorption and pharmacokinetic experiments. Physiology-based pharmacokinetic modelling (Simcyp® Simulator) is available to extrapolate experimental data to human pharmacokinetics. One of the major targets involves the biorelevant and predictive evaluation of absorption-enabling strategies, including solubilization and supersaturation of poorly soluble drugs. In this respect, Drug Delivery and Disposition has elaborated a ground-breaking approach for evaluating intraluminal drug and formulation behavior in humans, involving the aspiration and characterization of gastrointestinal fluids. All absorption studies are supported by well-developed analytical equipment (LC-UV, -fluo, -MS/MS) to assess concentrations of drugs, excipients and endogenous compounds in biological matrices.
In the field of hepatobiliary drug disposition and drug-drug interaction assessment, drug delivery and disposition has implemented the full spectrum of preclinical model systems of the liver including: rat/human liver microsomes, rat/human hepatocytes in suspension, sandwich-culture and 3D culture, cell lines transfected with hepatic drug transporters, isolated perfused rat liver and in vivo. Isolation and cryopreservation of attaching rodent hepatocytes and preparation of liver subcellular fractions is performed in-house. The research group has characterized several fluorescent transporter probes for evaluation and live imaging (by confocal microscopy) of drug transport processes in hepatocytes. Drug clearance prediction in special populations (e.g. pediatric), transporter-based pharmacokinetic boosting and liver unbound concentration assessment form major research objectives. The group has also developed and validated a holistic, hepatocyte-based in vitro model for identification of drug candidates showing risk for drug-induced cholestasis. The model has been mechanistically validated by bile acid profiling in sandwich-cultured hepatocytes. Computational expertise includes in vitro-in vivo extrapolation (IVIVE) algorithms for clearance prediction (SimCYP, R), compartmental and non-compartmental pharmacokinetic data analysis, as well as population pharmacokinetic analysis (NONMEM) of clinical exposure data. The group has taken the lead in generation of large in vitro transporter inhibition data sets leading to in silico models for structure-based prediction of transporter inhibition. Bioanalytical activities include LC-UV/FLUO/MSMS for preclinical and clinical samples.
Drug Delivery and Disposition is worldwide recognized for expertise in the field of amorphous materials and solid (molecular) dispersions of poorly soluble drugs. The process development and formulation of these systems are studied with the aim to correlate the physical structure of the drug-carrier (polymer) dispersions to their pharmaceutical performance and stability profile, and to correlate formulation and processing parameters to the resulting physical structure. Processing technologies that are being studied are spray drying, spray congealing, fluidized-bed bead coating, hot-melt extrusion, compression/compaction and mechano-chemical activation. Analytical techniques used for this purpose are thermal analysis (DSC, MDSC, hot-stage microscopy, isothermal microcalorimetry, solution calorimetry), X-ray powder diffraction, infrared spectroscopy, solid state NMR and in vitro (intrinsic) dissolution testing. In addition, Drug Delivery and Disposition is actively involved in the formulation and process development of drug delivery systems for intra-muscular and site-specific (oral) delivery. As part of the Center for Drug Delivery and Analysis of KU Leuven, Drug Delivery and Disposition is also involved in formulation development and preformulation studies for pharmaceutical companies.